The next generation

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During the past 20 years, Rakesh Kukreja, Ph.D., has mentored eight doctoral students, 12 graduate students, 21 postdoctoral fellows, 23 cardiology fellows and dozens of undergraduate, medical and high school students. Many of his past trainees are now enjoying successful careers in academia, industry, government and private practice.

Kukreja leads the nationally renowned program in molecular cardiology at the Virginia Commonwealth University Medical Center. He joined the cardiology faculty in 1988 as a research associate and is currently professor of internal medicine in the VCU School of Medicine and scientific director of the VCU Pauley Heart Center. He also has faculty appointments in the departments of biochemistry and molecular biology and physiology and biophysics.

With a long and distinguished track record of funding from the National Institutes of Health (NIH), the American Heart Association and various pharmaceutical companies, Kukreja’s research interests include cellular and molecular mechanisms of myocardial ischemia/reperfusion injury, gene therapy and cell signaling.

His research is focused on the mechanisms by which ischemia (heart attack) kills cardiac cells and the development of novel therapeutic strategies that can decrease the damage in the heart muscle. For the past 23 years, Kukreja has been working on the phenomenon of ischemic preconditioning, which is a natural way for the heart to protect itself.

In 2002, Kukreja and his colleagues discovered a new and potentially important use for the male erectile dysfunction drugs sildenafil (Viagra), vardenafil (Levitra) and tadalafil (Cialis). These drugs are potent inhibitors of phosphodiesterase-5 (PDE-5), an enzyme that regulates the levels of intracellular messenger molecule, cGMP. His research has shown that PDE-5 inhibitors show significant protection against damage from ischemia/reperfusion injury in animals.

In a major breakthrough, Kukreja and his colleagues further validated that sildenafil protected the heart against injuries caused by chemotherapeutic drug doxorubicin, both used to treat tumors and blood cancers. This work may lead to future development of a new group of compounds that could be evolved for both acute and chronic cardioprotective therapy against ischemia/reperfusion injury, hypertrophy and heart failure.

In observance of American Heart Month, VCU News asked Kukreja to talk about his research. In the United States, heart disease is the No. 1 killer of men and women.

What are your focused interests in research?

During the last 25 years, my work has remained focused on the discovery of novel therapeutic strategies to protect the heart against ischemia/reperfusion injury and heart failure. We initially performed a series of investigations that unraveled the molecular basis of ischemic preconditioning, a phenomenon where short episodes of ischemia and reperfusion render the heart resistant to a lethal ischemic insult.

One of the most intriguing findings of our research is the discovery that sildenafil (Viagra) and other phosphodiesterase-5 (PDE5) inhibitors induce a powerful protective effect against ischemia/reperfusion injury in the heart. More recently, we showed that PDE5 inhibitors protect the Type 2 diabetic hearts against myocardial infarction and inflammation.

In addition, we described the protective effect of rapamycin against ischemia/reperfusion injury in the heart for the first time. Sirolimus® (rapamycin) is a clinically approved drug to prevent organ rejection, inhibition of restenosis after angioplasty and for treatment of several advanced cancers.

How do you hope to make an impact with your research?

My hope is that our research would have impact in developing novel treatments for cardiovascular diseases across the globe. I am fortunate that our groundbreaking studies have been very helpful in generating tremendous interest in the scientific community in discovering new clinical uses of PDE5 inhibitors for treatment of cardiovascular diseases.

Our work has helped in initiating several NIH-sponsored and investigator-initiated clinical trials in patients with heart failure, Type 2 diabetes, Duchenne muscular dystrophy patients with cardiac disease and cancer patients receiving doxorubicin at the VCU Massey Cancer Center.

What drives you?

It is the persistent quest for new knowledge that drives me to work day after day without any feeling of tiredness.

I enjoy several things about research. It is the freedom to pursue new ideas, to formulate novel hypotheses for the critical questions and the actual execution of the experimental plan. The recognition of our research by the peers gives me immense satisfaction as well. Also, I enjoy contributing to the peer-review system by reviewing papers, research grants from the NIH and other international funding agencies.

These activities give me the opportunity to stay on top of the cutting edge research, identify the best science for funding and to improve the quality of work published in the research journals.

Does VCU provide a good home for your research endeavors?

I came to Richmond because of my family and found a postdoctoral position in the cardiology division. At that time, I never knew that the opportunity I got at VCU would transform my academic life forever.

I found the research environment at VCU highly conducive for creativity, and my colleagues in the laboratory were extremely helpful and always went out of their way to facilitate my research. I enjoy working at VCU because of the outstanding research environment, collaborative spirit among faculty and state-of-the art research facilities. Because of the great reputation of VCU, I was able to have excellent graduate students, postdoctoral and cardiology fellows who truly played a key role in the development of my research program at VCU.  

Do you enjoy your role as a mentor to junior research faculty?

I love mentoring the junior faculty. I enjoy discussing experiments, the research data and writing about papers and future innovative ideas that may have impact in contributing to the cardiovascular disease.

I currently mentor three highly talented faculty members, Drs. Fadi N. Salloum, Anindita Das and Lei Xi. It gives me great satisfaction when they have success in funding of their grants and acceptance of their manuscripts, especially in top-tier journals. For me, it is truly a joy to watch them grow in their careers, whether it is an invitation to review the grants for a study section, appointment in the editorial boards or other key positions in academia.  

What has been your biggest accomplishment?

My biggest accomplishment is the development of our world-renowned research program in cardiovascular research at the VCU Pauley Heart Center. I began my research career in 1984 as a postdoctoral fellow with my mentors, Dr. Michael Hess and Dr. Hermes Kontos, two world class physician scientists in the Division of Cardiology. Both of them truly set the path for me in the cardiovascular research area.

I am very proud that the labs where I spent most of my research career since my joining VCU is now a state- of-the-art, well-equipped heart research facility, thanks to $ 5 million renovation grant funding from the NIH. We are in such a great situation where we have the capability to attract talented investigators to expand our research enterprise to another level and train the next generation of cardiovascular researchers.